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Science. 2017 Jun 9;356(6342):1084-1087. doi: 10.1126/science.aaf7497.

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.

Author information

1
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
2
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands.
4
Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
5
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Italy.
6
Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy.
7
Department of Neuroscience, Erasmus Medical Centre, 3000 CA, Rotterdam, Netherlands.
8
Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands.
9
Toxys B.V., Robert Boyleweg 4, 2333 CG, Leiden, Netherlands.
10
Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Sciences, 1105 BA, Amsterdam, Netherlands.
11
European Centre for Brain Research-Institute for Research and Healthcare (IRCCS) Santa Lucia Foundation, Via del Fosso del Fiorano 65, 00143 Rome, Italy.
12
Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.
13
Department of Psychiatry, Erasmus University Medical Centre, 3000 CA, Rotterdam, Netherlands. m.van.der.stelt@chem.leidenuniv.nl s.kushner@erasmusmc.nl.
14
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, Netherlands. m.van.der.stelt@chem.leidenuniv.nl s.kushner@erasmusmc.nl.

Abstract

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

PMID:
28596366
PMCID:
PMC5641481
DOI:
10.1126/science.aaf7497
[Indexed for MEDLINE]
Free PMC Article

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